Ignored and invisible! When the authors of the Chief Medical Officer’s report of 2002 coined that phrase they were referring to the exclusion of the most severely ill people with ME from community and social care provision. However, the same description also holds true for mainstream scientific research.

A cursory glance at the existing scientific literature on ME (largely held in electronic databases — mainly MEDLINE — and specialist resources like the downloadable database of some 4000 abstracts at the Research UK website — available here) reveals the virtual absence of information on the most severely affected people.

The Table below gives the number of articles (loosely defined) published for some randomly-chosen illnesses, and it shows two things. First, that ME is a Cinderella illness compared with other comparable chronic conditions in terms of volume of research publications, and second, that research on the severely ill is a rarity in most illnesses, including ME. In practice, very few of these studies deal specifically with the most severely ill people with ME/CFS (i.e., the housebound, bedbound or immobile).

Table. Number of MEDLINE entries (rounded) to August 2013 for a range of illnesses including ME/CFS, including percentage of these relating to severe illness (variously defined)

Illness

Total no. of articles

Estimated no. of “clinical trials”

Estimated trials on the severely ill

Diabetes

446,000

28,900

0.3%

Rheumatoid arthritis

117,400

7,100

0.4%

Multiple sclerosis

57,200

3,200

0.3%

Lower back pain

26,100

3,200

0.6%

Irritable bowel syndrome

8,300

900

0.5%

ME/CFS

6,200

400

0.5%

The point is that severely affected people with ME are doubly disadvantaged: not only is this illness under-researched compared with other chronic conditions, but the most severely ill group of patients is under-represented in what little research is done. In fact, very few studies exist, and all define ‘severe illness’ in different ways, complicating interpretation of the findings. And specific laboratory-based or experimental studies on severe sufferers are as rare as hens’ teeth.

The findings so far…

For the record, the studies in question that present some kind of patient data (albeit with varying definitions of ‘severe’ illness) include:

a) Effect of specialist hospital programmes — The CFS team at Oldchurch Hospital in Essex surveyed the 72 most severely affected CFS patients admitted 1990–98. They found that 46% had actually been discharged with an alternative diagnosis to CFS, that patients with a symptom duration greater than five years appeared to improve, and that the level of severity did not preclude improvement (2). In a subsequent quasi-experimental study, this team found that their occupational therapy intervention significantly improved perception of health and “length of time tired” in patients compared with waiting list control patients (3).

The Oldchurch team have continued to audit the outcomes of their work, and the most recent of these (December 2003) examines 24 severely affected patients following an inpatient stay. While two-thirds saw their severity rating improve by one or two grades, on a scale of one to five, a third saw no change in their level of severity. However, 50% reported a positive shift in mood and 87% described an increase in their quality of life post-admission. Using a patient feedback questionnaire, 39% rated their satisfaction with the CFS service as 10/10, with just 4% giving a score of less than five.

Two similar, smaller outcome studies (4, 5) also reported appropriate multidisciplinary inpatient rehabilitation to be beneficial, at least in terms of “functional ability”, to the majority of severely affected patients. (Five out of six patients “functionally improved” in the Chalder study and 17 out of the 19 followed up in the Essame study).

b) An experimental study of cardiac output — Researchers examining 38 patients found that participants with “severe” CFS had significantly lower cardiac output than the controls and less ill patients (6). Post-exertional fatigue and flu-like symptoms of infection clearly differentiated the patients with severe CFS from those with a less severe presentation, and were predictive of lower cardiac output. These results, say the researchers, “provide a preliminary indication of reduced circulation in patients with severe CFS”.

c) Investigating longer-term outcomes — One study has evaluated the natural history of CFS in a severely ill group of 24 patients at three points in time (7). Over the four years of the study, thirteen patients remained severely ill, nine improved but still fulfilled the 1994 case definition for CFS, and one recovered. Illness duration, mode of onset, psychiatric status/depressed mood at intake, or chemical sensitivity did not appear to predict illness outcome. Not surprisingly, mood improved for those patients whose illness lessened. The researchers concluded that the prognosis for full recovery was extremely poor for the most severely ill subset of CFS patients.

Another outcome study of severely affected children (8) followed up 25 children using child-parent interviews. After nearly four years, two-thirds of the children had recovered, and none had developed any other medical conditions, allowing tentative conclusions that severe illness can cause severe handicap but that most children recover.

In addition, one report has detailed outcomes for two wheelchair-bound CFS patients treated by a “pragmatic intervention” consisting of more than 50 face-to-face or telephone contacts with a therapist over approximately two years. By the end of the intervention, both patients were reported to be free of their wheelchairs and leading “relatively independent existences” (9). And two reports have also been published giving results from the Case History Research On Myalgic Encephalomyelitis (CHROME) database (10, 11).

Why is there so little research?

The CMO report defined the severely affected as those “patients whose physical disability is most severe, leading to serious restrictions in mobility and functioning. In many, these restrictions are accompanied by other markers of severity, such as cognitive impairment or prolonged course” (Section 3.4.3). Clearly, anyone who is severely affected would struggle to attend hospital-based investigations, which often require multiple visits.

However, even if they could attend, they might well be excluded for other reasons, such as the presence of ‘co-morbid’ illnesses which often accompany severe ME and its consequences (e.g., long term immobility with accompanying deconditioning, susceptibility to infection, etc.), or their inability to fulfill the requirements of a trial (e.g., perform graded exercise or stop current medications). Sensible though these restrictions might seem to healthy young researchers, they are little comfort to severely ill people who wish to see scientific progress within their own lifetime! Of course, it is feasible to conduct a ‘pragmatic’ study in which a ‘treatment’ is given to a large group of diverse patients in their own homes, and the results of one of these — the FINE trial — were published in 2010.

The FINE trial

From 2003–9, the vast bulk of the £3.1 million spent by the Medical Research Council on ME/CFS research went into two clinical trials (see the analysis). The largest was the PACE trial which compared cognitive-behavioural therapy (CBT), graded exercise (GET) and pacing. The other was the FINE (Fatigue Intervention by Nurses Evaluation) trial in which severely affected patients were randomly allocated to one of three groups: “pragmatic rehabilitation” – a nurse-led self-help approach which included elements of CBT and GET delivered in the patient’s home; supportive listening; or usual care provided by their GP.

The overall results of the FINE trial were reported in 2010 in the British Medical Journal. A total of 296 adults with ME/CFS were enrolled, and after 20 weeks of treatment, patients receiving pragmatic rehabilitation were significantly less fatigued and depressed, and were sleeping better than those who received usual care (although there was no difference in physical functioning). However, one year later there was no longer any difference between these two patient groups. Thus, while pragmatic rehabilitation appeared to help fatigue and depression in the short term, over a longer period it was no better than usual care provided by a GP (with supportive listening having no benefits at all).

Subsequently, a cost-effectiveness analysis of the FINE trial results was published in 2013 in the journal BMC Family Practice. This ‘within trial analysis’ compared the costs and quality adjusted life years (QALYs) in the 3 treatment groups, concluding that “pragmatic rehabilitation” was unlikely to be cost-effective. As the authors’ concluded, any benefits generated by pragmatic rehabilitation were unlikely to be of sufficient magnitude to warrant recommending this treatment for this patient group on cost-effectiveness grounds alone.

Were these negative results a surprise? Not really, given that pragmatic rehabilitation does not, and was never intended to, address the pathophysiological basis of disease in these severely ill people. The real surprise was that most of the MRC’s inadequate grant-spend on ME/CFS from 2003–9 went on trials of non-specific management and coping strategies at the expense of truly biomedical research, the reverse of the situation in other illnesses such as MS or rheumatoid arthritis. Fortunately, the MRC unveiled a ‘pathophysiology’ call for applications in 2011, culminating in the award of grants for research that was overwhelmingly ‘biomedical’ rather than ‘psychosocial’ in nature. It was heartening to see that the MRC made five discrete grant awards under this call, at a cost of approximately £1.65 million

A scandalous situation overall

As regards biomedical research overall, there is a serious mismatch between published studies and the extent of the human problem. While we know very little about the incidence and prevalence of ME generally, the proportion of patients with severe illness has been variously estimated at 25% (hence, the “25% ME Group for Severe Sufferers”), one third who experience “a severe and debilitating downhill course” (Dr Melvin Ramsay), and 34% as reported by Action for ME’s Members Survey of November 2000. This evidence, conjoined with findings from the CMO’s report that “a minority… remain permanently, severely disabled and dependent on others”, illustrates the scale of the problem that still needs to be addressed.

To put it bluntly, if 30% of ME patients in the UK are severely affected at any one time, this means that between 36,000 and 72,000 people are severely ill. For such numbers to be so under-investigated by scientists, albeit for practical reasons, is surely scandalous — yet this is the situation. The CMO’s report concludes that, “Current provision of services falls well below what is needed for the vast majority of severely and very severely affected patients” (Section 3.4.3.1).

Stabbing in the dark

It’s sobering to consider that, after decades, we still understand very little about the origin and outcome of severe illness in ME. Yes, we know that severe illness (and the other medical conditions that accompany it) complicates matters. We know that the prospects for recovery tend to be worse for those most severely affected, whether adults or children, and that specific viral triggers, duration of illness and socioeconomic status have all been associated with the severity of the clinical picture. Most importantly, we know that the cumulative impact of severe illness over many years, where there is no sense of improvement, is profound.

Yet, even these rather unsurprising findings are based on a relatively small number of investigations, and as such cannot be called definitive. The truth is that, after some stabbing in the dark, the complexity, severity and longevity of the illness are still only dimly perceived. The most meaningful information often comes from the dedicated efforts of specialist groups that have collected data on their severely ill members or clients (see below).

Case History Research on Myalgic Encephalomyelitis (CHROME)

Soft data and hard experience

Clearly, community-based surveys can be very useful for describing the experiences of people with severe ME, and might be important for hypothesis generation; i.e., they may uncover areas of concern (such as the lack of community care provision), and highlight areas where new research is needed (such as the urgent need for pain relief). In short, they can provide a systematic record of individual suffering, and point to ways to alleviate it.

However, there is a very real problem about the meaning of survey data generally to medical/scientific professionals outside of ME patient circles. Strange as it may seem, surveys come low (grade III or lower) in the hierarchy of research designs, since they are not valuable for determining causation, or the ‘specific effect’ of treatment. In addition, charities’ in-house patient surveys have many limitations. First, most of the data has usually not been collected using validated, standardised outcome questionnaires that can be used for comparison with other studies or illnesses. Then there is the problem of poor response rates that range from 66% down to 31% in recent ME group surveys, raising the whole question of the meaning of non-responses, a statistical minefield (fortunately) beyond the scope of this article.

But the greatest flaw in the eyes of suspicious outsiders is the ‘Christine Keeler’ effect — “they would say that, wouldn’t they”. Since the survey data emanates from a so-called self-selecting group of people with self-reported symptoms, a question mark hangs over the veracity of the data, especially if — as some psychosocial professionals maintain — claiming to be severely ill can help maintain a sickness role and acquire state benefits.

A good example of the difficulties of getting such information published came in 2002 when the 25% ME Group and ME Research UK tried to publish a small table of data as a letter in the Journal of the American Medical Association. To say there was a lack of interest is an understatement: in the end, the data was presented in ME Research UK’s report Unhelpful Counsel (read it here), and so was seen by, at most, a few hundred people instead of the 200,000+ members of the American Medical Association, the sort of audience the most severely affected patients, and the data, deserved. These problems with survey data are not specific to ME, by the way, but this illness — with its peculiar combination of public scepticism and professional uncertainty or outright distain — is probably more at risk than most.

Preparing to climb the mountain

Given that surveys are things that patient charities are well-positioned to undertake, there are in fact some simple things that groups representing the severely ill can do to facilitate the acquisition of valid information. One is to include with their custom-designed questionnaires at least one recognised validated outcome measure, such as the Medical Outcomes Study SF36, a short, easily-completed measure of quality of life that allows direct comparison with other illnesses and other types of ME patients. Again, groups could be willing to supply data for analysis by independent organisations though, of course, the ideal situation is for a university department or other professional group to be involved from the outset.

However, a most useful advance would be a national epidemiological investigation of the true prevalence and impact of severe ME. Indeed, as the CMO report made clear, the organisation of primary care services in the UK offers a unique opportunity to undertake prevalence studies on the national scale needed to generate the requisite data.

To end where we began, the same report stated in 2002 that “care of people who are severely affected is an urgent challenge”. Scientific investigation of the severely affected — their clinical status, experience of illness and treatment — is also a challenge that should be swiftly met.

Ignored and invisible, maybe — but it doesn’t have to be like that. Energy, vision and funding can transform any situation.

References

A Report of the CFS/ME Working Group. Report to the Chief Medical Officer of an Independent Working Group. February 2002. (pdf here)